Discipline: Biological Sciences
Andy Madrid - University of Wisconsin - Madison
Co-Author(s): Ligia A. Papale, Qi Zhang, Sisi Li, Kailei Chen, Sunduz Keles, and Reid S. Alisch, University of Wisconsin - Madison, Madison, WI
Autism spectrum disorders (ASD) describe a scope of conditions characterized by deficits in social communication and interaction, repetitive behaviors, and cognitive delays that affect about 1% of the world’s population. Genetic components of ASD are highly heterogeneous and only characterizable in about 15% of ASD cases. Environmentally sensitive epigenetic mechanisms (i.e. DNA methylation) have been reported in numerous genetic disorders associated with autism, suggesting that epigenetic mechanisms involving gene and environment interactions might be a common pathway for many cases of autism. Early life stressors such as abuse/neglect increase physiological sensitivity to even mild adversities later in life and are associated with alterations of DNA methylation and gene expression. Since 5-hydroxymethylcytosine (5hmC) is a novel environmentally sensitive DNA modification that is highly enriched in neurons and is linked to brain-related disorders, we hypothesized a role for 5hmC (e.g., regulation of gene expression) in the complex etiology of autism. To test this hypothesis, we examined a mouse model of autism (i.e., Cntnap2-/-, homozygote), which has deficits in core autism features, while heterozygote mice develop normally. Pregnant dams were subjected to 7-days of variable stress beginning at embryonic day 12. Behavioral assessment of adult offspring revealed that female heterozygotes develop autistic-like phenotypes. Next, we examined the gene by environment interaction by determining the contribution of genome-wide DNA methylation (5hmC) and gene expression (i.e., via RNAseq) in the same animals. DNA and RNA were extracted from striatal tissue of heterozygous and wild-type offspring with and without prenatal stress. Sequence data was mapped to the mouse genome and MOSAiCS was used to analyze differential 5hmC levels, while the Tuxedo Suite was used to find differentially expressed genes. These analyses revealed several known autsim-related genes (e.g., Oxt and Gabra1) to have both differential expression and differentially hydroxymethylated regions (DhMRs). In conclusion, these data suggest that prenatal stress affects gene expression by altering 5hmC, which, in turn, may mediate the observed autistic-like phenotypes in mice prone to develop mental illness. Further investigation of the functional role of 5hmC in stress-induced gender-specific development of brain disorders is underway.AM_ERN Conference Abstract.docx
Funder Acknowledgement(s): We would like to thank the WISPIC animal facility. Funding was supported in part by the University of Wisconsin-Madison department of Psychiatry, the University of Wisconsin Neuroscience training grant 732-GM007507, NARSAD Young Investigator Grant from the Brain & Behavioral Research Foundation #22669, and NIH grants HG003747, HG007019, and U54AI117924.
Faculty Advisor: Reid S. Alisch, firstname.lastname@example.org